Abstract

Glioblastoma (GBM) is a primary brain cancer that is resistant to all treatment modalities. This resistance is due, in large part, to invasive cancer cells that disperse from the main tumor site, escape surgical resection, and contribute to recurrent secondary lesions. The adhesion and signaling mechanisms that drive GBM cell invasion remain enigmatic, and as a result there are no effective anti-invasive clinical therapies. Here we have characterized a novel adhesion and
signaling pathway comprised of the integrin alphavbeta8 and its intracellular binding partner, Spinophilin (Spn), which regulates GBM cell invasion in the brain microenvironment. We show for the first time that Spn binds directly to the cytoplasmic domain of beta8 integrin in GBM cells. Genetically targeting Spn leads to enhanced invasive cell growth in pre-clinical models of GBM. Spn regulates GBM cell invasion by modulating the formation and dissolution of invadopodia.
Spn-regulated invadopodia dynamics are dependent, in part, on proper spatiotemporal activation of the Rac1 GTPase. GBM cells that lack Spn showed diminished Rac1 activities, increased numbers of invadopodia and enhanced extracellular matrix (ECM) degradation. Collectively, these data identify Spn as a critical adhesion and signaling protein that is essential for modulating GBM cell invasion in the brain microenvironment.
Implications: Tumor cell invasion is a major clinical obstacle in glioblastoma and this study identifies a new signaling pathway regulated by Spinophilin in invasive glioblastoma.